Process for the preparation of 4-amino-2-methylpyrimidine 5-carboxamide

ABSTRACT

This invention is directed to a process for the preparation of 4-amino-2-methylpyrimidine 5-carboxamide from 2-cyano-3-di-(lower alkyl)amino acrolein. The 4-amino-2-methylpyrimidine 5carboxamide is a known compound which is a valuable intermediate in the synthesis of thiamine.

United States Patent Leimgruber et a].

[ Aug. 26, 1975 PROCESS FOR THE PREPARATION OF 4-AMlNO-Z-METHYLPYRIMIDINE S-CARBOXAMIDE Inventors: Willy Leimgruber, Montclair',

Manfred Weigele, North Caldwell,

both of NJ.

Assignee: Hoffmann-La Roche Inc., Nutley,

Filed: Nov. 7, 1973 App]. No.: 413,735

Related US. Application Data Division of Serv No. 223,703, Feb. 4, I972, Pat, No, 3,792,076, which is a division of Ser. No. 56,715, Aug. 7, I970, Pat. No. 3,689,498.

US. CL... 260/256A N; 260/256.6; 260/307 R;

260/4654; 260/4655 R Int. Cl. C07D 239/42 Field of Search 260/256.4 N

[56] References Cited UNITED STATES PATENTS 3,487,083 l2/l969 Cresswell et al 260/2564 OTHER PUBLICATIONS Theilheimer; Synthetic Methods of Organic Chemistry; 1954; Vol. 8; 457.

Primary Examiner-Richard J. Gallagher Assistant ExaminerMary C. Vaughn Attorney, Agent, or Firm-Samuel L. Welt; Jon S. Saxe; William H. Epstein 5 7 ABSTRACT 3 Claims, No Drawings PROCESS FOR THE PREPARATION OF 4-AMlNO-2-METHYLPYRIMIDINE S-CARBOXAMIDE CROSS REFERENCE TO RELATED APPLICATIONS This is a division of application Ser. No. 223.703 filed Feb. 4. 1972. now U.S. Pat. No. 3.792.076 which is a division of U8. Pat. Application Scr. No. 56,7l5. which was filed on Aug. 7. I970 now US. Pat. No. 3.689.498.

BACKGROUND OF THE INVENTION The compound 4-amino-2-methylpyrimidine 5- carboxamide, an important intermediate in the synthesis of thiamine. has been synthesized via cyanoacetamide. This process suffers from the disadvantage that cyanoacetamide has been a difficult material to synthe size economically Generally. cyanoacctamide is synthesized from a-chloroacetic acid in four steps. The use of a four-step synthesis provides obvious drawbacks as far as yields and economies are concerned. Furthermore. chloroacetic acid is a rather expensive starting material. Therefore, it has long been desired to provide a simple and economic means to synthesize 4-amino-2- methyl-pyrimidine 5-carboxamide from inexpensive and readily available starting materials.

SUMMARY OF THE INVENTION In accordance with this invention. it has been found that 4-amino-2-methylpyrimidine S-carboxamide. which has the formula:

CONI'I can be easily synthesized from 2-cyano-3-di(lower alkyllamino acrolein which has the formula:

wherein R. and R are lower alkyl.

The compound of formula II is simply and economically synthesized from a compound of the formula:

wherein R, and R are as above; and R is lower alkyl; is condensed at a temperature of at least C. with acetonitrile. In accordance with the second method of producing the compound of formula III above. a compound of the formula:

wherein R, and R are as above; is treated with a hydrogen acceptor at a temperature of at least 50C. in the presence of a dehydrogenation catalyst.

DETAILED DESCRIPTION As used throughout the specification, the term lower alkyl" includes both straight and branched chain alkyl groups containing from 1 to 6 carbon atoms such as methyl, ethyl. propyl, isopropyl, and the like. As used throughout the specification. the term halide" includes all four halide ions such as bromide, chloride, fluoride or iodide.

The reaction of acetonitrile with the acetal of formula IV to form the compound of formula II] is carried out at a temperature of at least 80C. Generally. it is preferred to utilize a temperature of from C. to 250C. in carrying out this reaction. While this reaction can be carried out at atmospheric pressure, superatmosphcric pressures are utilized when higher temperatures are utilized. This reaction can be carried out without the need for utilizing any solvent. However, if desired, an inert organic solvent can be utilized. Any conventional inert organic solvent such as benzene, toluene, N.N-dimethylformamide, can. if desired be utilized in carrying out this reaction.

The second method of preparing the compound of formula III above is by treating a compound of formula V above with a hydrogen acceptor at a temperature of at least 50C. in the presence of a dehydrogenation catalyst. Any conventional dehydrogenation catalyst can be utilized in carrying out this reaction. Among the preferred dehydrogenation catalysts which can be utilized in this reaction are palladium, Raney nickel and cupric chromite. In carrying out this reaction. any conventional hydrogen acceptor can be utilized. Among the preferred hydrogen acceptors is oxygen which can be supplied by carrying out the reaction in the presence of air. Alternatively, the oxygen can be supplied in the form of bottled oxygen. Other hydrogen acceptors which can be advantageously utilized in this process are aliphatic ethers containing at least one ethylenic moiety bound to the oxygen atom and having from 3 to 15 carbon atoms such as methyl vinyl ether and cyclic ethers such as dihydropyran.

In converting the compound of formula V above to the compound of formula III above, no solvent need be present. Generally. in carrying out this reaction. a temperature of at least 50C. should be utilized with temperatures of between 80C. to 200C, being preferred. If high temperatures are utilized, the reaction may be carried out under superatmospheric pressure.

The compound of formula III is converted to the compound of formula II via an intermediate of the formula:

actants may be used in any molar ratio. In carrying out this reaction, temperatures of from about lC. to +lOC. are utilized. Generally, it is preferred to carry out this reaction in the presence of an inert organic solvent. Any conventional inert organic solvent can be uti lized. However, the preferred solvents are the halogenated hydrocarbons such as chloroform, dichloromethane, l,2-dichloroethane, etc. In carrying outthis ,reaction, any of the lower alkyl formamides, preferably dimethyl formamide can be utilized. Among the. preferred inorganic acid halide condensing agents which can be utilized in accordance with this invention are included phosphorus oxychloride, phosgene, thionyl chloride, phosphorus pentachloride, etc. i I,

The compound of formula VI above is converted into the compound of formula I] above by raising the pH of an aqueous solution containing the compound otgfor mula Vl above to a value of from 7 to 9. This ,is accornplished by treating the compound of formula \(I above with an aqueous alkaline medium sufficient to faise the pH to a range of from 7 to 9. Any conventional inorganic base such as sodium hydroxide, potassium hydroxide, etc. can be utilized as the alkaline medium to provide a pH within the range of from about 7 to 9., in carrying out this reaction, temperature andpressure are not critical and this reaction can be carried out at,

room temperature and atmospheric pressure. If desired, elevated or reduced temperatures can be utilized.

The compound of formula II is converted to the e ompound of formula I via the following reaction scheme:

wherein R and R are as above; and X' I is a halide ion or sulfate ion.

In accordance with this invention. the compound of formula II above is converted into the compound of formula Vlll via reaction step (a) by reacting the compound of the formula ll with a hydrohalic acid addition salt or a sulfate salt of hydroxylarnine. This reaction is carried out at a temperature of from 0C. to 25C. in an inert organic solvent. Any conventional inert organic solvent can be utilized in carrying out this reaction with solvents such as lower alkanols including methanol, ethanol, or isopropanol being generally preferred. The reaction ofstep (a) is simply carried out by mixing the hydrohalic acid addition salt or sulfate salt of hydroxylamine with the compound of formula ll above in an inert organic solvent while maintaining the temperature of from O-30C. in carrying out this reaction of step (a), the preferred hydrohalic acid addition salt of hydroxylamine is hydroxylamin'e hydrochloride. In this reaction, the compound of formula II is reacted in equimolar amounts with the salt of hydroxylamine. However, if desired, an excess of the compound of formula ll orthe salt can be present in the reaction medium.

The compound of formula Vlll is converted to the compound of formula [X by heating the compound of formula Vlll in an inert organic solvent to a temperature of from 30C. to the reflux temperature. In carrying out the reaction of step (b), any conventional inert organic solvent can be utilized. Generally, it is preferred to utilize the same solvent that was utilized in carrying out the reaction of step (a).

In accordance with a preferred embodiment of this invention, the compound of formula ll can be directly converted to the compound of formula 1X. This is accomplished by simply heating the compound of formula ll with a hydrohalic acid addition salt, or sulfate salt of hydroxylamine at a temperature of from 30C. to the reflux temperature. This reaction is preferably carried out in the presence of an inert organic solvent. Any conventional inert organic solvent can be utilized. Among the preferred inert organic solvents are the alcohols such as ethanol, methanol or isopropanol. The compound of formula ll can be reacted in equimolar quantities with the salt of hydroxylamine. However, an excess of the compound of the forrnula ll above or the hydroxyl amine salt can be present in this reaction.

The compound of formula lX is converted to the compound of formula I, via reaction step (c) by reacting the compound of formula lX with acetamidine. The acetamidine that is utilized in this reaction is prepared by neutralizing an acetamidine hydrohalic acid addition salt. This neutralization of the acetamidine hydrohalic acid addition salt to produce the acetamidine uti lized to react with the compound of formula IX is carried out by addition :(if a base. Any conventional base such as an alkali metal hydroxide or alkali metal lower alkoxide can be utilized. Generally, the neutralization reaction is carried out in the presence of an inert organic solvent. Any conventional inert organic solvent can be utilized. Among the preferred inert organic solvents are included lower alkanols such as methanol or ethanol. Generally, this neutralization reaction is carricd out at temperatures from between C. to 30C.

In preparing the compound of formula], the acetamidine, which is liberated in an organicsolv entsolution by the neutralization of the hydrohalicacid salt of acetarnidine, is mixed with the compound "oi" formula IX. This mixture is then allowed to stand fora period of at least hours at a temperature of 0 to 30C.. preferably room temperature. For bestresultsi it has been found preferable to keep this reaction inixture'at this temperattire for a period of from to hours. lfde'site'd, the reaction mixture can be kept at 01m for' a period of .36 hours or longer. Since rioadditio'rjalpeneticial results are achieved by keeping the reaciion mixture standing at this temperature rangefor such prolonged periods, standing times of greater than 36 hours are seldom utilized. After this period, the reaction mixture is heated to a temperature of from 40C. to the reflux temperature to carry out the conversion to the, com-.

EXAMPLE I Dchydrogenation of dimethylaminopropionitrile to dimethylaminoacrylonittile The catalytic dehydrogenation of dimethyl'aminopropionitrile was carried out under the" following conditions:

Hydrogen Reaction Reaction Acceptor Catalyst Temperature Tim:

Air IUZ Raney Rclux: about 6 hours nickel l l5C.

Air CuCqO, 3-24 hours (H CHOC'ILCR palladium on SOC. 24 hours carbon t It i Dihydropyran palladium on carbon Rcllux: about 24 hours t Ill; l 30C.

Dihydmpyran palladium on carbon Reflux 40 hours In the above reaction a reaction mixture was prepared containing the catalyst and dimethylaminopro pionitrilc. Where an ether hydrogen acceptor was utilized. the hydrogen acceptor was present in a molar amount often times the moles of dimethylaminopropionitrilc in the reaction mixture and the reaction was carried out under nitrogenv In the cases where air was used, the reaction was carried out by exposing the reaction mixture to the atmosphere. Thc catalyst was present in an amount of about 10% by weight or 30% by weight based upon the weight of the dimethylaminopropionitrilc as indicated above. The final product obtained by vapor phase chromatography was dimethylaminoacrylonitrilc. This product distilled at l l5C. at 3mm Hg.

7 EXAMPLE 2 Preparation of 3-dimethylaminoacrylonitrile 173.0 g. of the diethylacetal of dimethylformamide (1.18 moles) and 400 ml of acetonitrile were placed in a 1200 'ml. autoclave. Air was removed from the autoclave flushing with nitrogen, and after purging charged to 50 psi". with nitrogen. The reaction was carried out for 36 hours at.l 50C. Upon completion of the reaction, excess acetonitrile was removed by vacuum distillation using a rotary evaporator at a vacuum of 135 mm Hg. and a waterbath temperature of 60C. maximum. The remaining residue was fractionated using a 24- inch Vigreaux column.- After discarding a small first fraction, the material boiling at l l5C. and

3.0 mm Hg was collected. This material was 3- dimethylaminoacrylonitrile.

EXAMPLE 3 10 ml of N,N-dimethylformam'ide were stirred zit-4 to -7 and 10 ml. of phosphoroxychloride were'added dropwise in such a rate as to maintain the reaction temperature below 0. The resulting semi-solid reaction mixture was diluted with ml. of IQZ-dichloroethane. On warming to room temperature, a clear amber solution was obtained. The solution was cooled to 8 to l0C. and 5.9l g. of B-dimethylamino-acrylonitrile, dissolved in IS ml of l,2-dichloroethane were added dropwise with stirring within l5 minutes. After removal of the solvent in vacuo a semicrystalline residue was obtained. The rnaterial was dissolved in 20 g of ice/water and 8. l g. of sodium perchlorate were added to this solution. On cooling (3-dimethylamino-2-cyano-2- propenl -yliderie )-dimcthyla mmonium perchlorate as crystals, (m.p l39-l42) wasobtained.

EXAMPLE 4 Preparation of 2-cyano-3-dimethylaminoacrolein 36 ml. (0.465 mole) of N,N-dimethylformamide were stirred at 0 and 36 ml. (0.392 mole) of phosphorus oxychloride were added dropwise (a salt/ice bath was used in order to keep the reaction mixture at 0). I

To the stirring semi-solid. faintly colored reaction mix ture was added 300 ml. of l,2-dichloroethane. Upon warming to room temperature by means of a water bath (25), a clear solution resulted which was cooled to 7 with an icesalt bath. A solution of 30 ml. (0.293 mole) of B-dimethylaminoacrylonitrile in ml of 1,2- dichloroethanetwas added dropwise keeping the temperature between -4 to 7. The addition required about l hour. The cooling bath was removed and the clear amber reaction mixture allowed to come to room temperature. The reaction mixture was transferred to a 2 liter, round bottomed flask and the solvent removed in vacuo leaving a semi-solid orange colored residue. A I00 g. of ice was added to the residue which gradually dissolved with evolution of heat. The solution was transferred to a beaker and the pH adjusted to 8.4 by adding carcftflly 2N sodium hydroxide (EH5 ml. were required) to the. stirred solution at l5-2()C. The resuiting solution was extracted with ethyl acetate in a liquidliquid extractor overnight. The ethyl acetate extract was cooled, the crystals which had separated were filtered off. washed with cold ethyl acetate and dried in vacuo. affording crude 2-cyano-3- dimethylaminoacrolein. as deep yellow prisms, m.p. l43l44C. This material was dissolved in 500 ml. of hot water. treated with 2 g. of norite. the solvent removed in vacuo and the residue crystallized from abso' lute ethanol. producing the pure product in the form of light yellow prisms, m.p. l43-I44C.

EXAMPLE 5 Preparation of 5-amino-4-isoxazolylmethylene dimethyl ammonium chloride EXAMPLE6 Preparation of 3-dimethylamino-Z-cyanoacrylamide A mixture of 500 mg. of S-amino-4- isoxazolylmethylene dimethyl ammonium chloride in 2 ml of methanol was heated to reflux for 45 minutes. After this period the reaction mixture was filtered while still hot. On cooling to room temperature, there precipitated from the filtrate. 3-dimethylamino-2- cyanoacrylamide, m.p. l70-l74C.

EXAMPLE 7 Preparation of 3-dimethylamino-2-cyanoacrylamide To a solution of 24.8 g. of 2-cyano-3-dimethylaminoacrolein in I00 ml of methanol was added a solution of 13.9 g hydroxylamine hydrochloride in [00 ml of methanol. The mixture was heated to reflux for 45 minutes and then filtered while still hot. On cooling to room temperature there precipitated from the filtrate 3- dimethylamino-Z-cyanoacrylamide, m.p. l 70-l 74C.

EXAMPLE 8 Preparation of 4-amino-Z-methylpyrimidinc S-carboxamidc To a cooled solution of 1.0 g acetamidine hydrochloride in ID ml methanol was added a solution of 500 mg sodium methoxide in 5 ml methanol. The resulting mixture was filtered. The filtrate was allowed to come to room temperature (20C) and then l.4 g of 3- dimethylamino-Z-cyano-acrylamide were added with stirring. The mixture was kept at room temperature (20C) for 24 hours. It was then heated to reflux for 1 hour and filtered hot. ()n cooling, 4-amino-2- methylpyrimidine-3-carboxamide crystallized from the filtrate. m.p. 265267C.

We claim:

I. A process for producing 4-amino-2- methylpyrimidine'fi-carboxamide comprising the steps of reacting 3-di(lower alkyl)amino-Z-cyanoacrylamide of the formula:

wherein R, and R, are lower alkyl having from I to 6 carbon atoms; with acetamidine in an inert organic solvent for at least 5 hours at a temperature of from 0 to 30C. and thereafter heating the resulting reaction mixture to a temperature of from 40C. to reflux to form said pyrimidine.

2. The process of claim I wherein said mixture is prepared by first neutralizing in an inert organic solvent a hydrohalic acid addition salt of acetamidine with a base and thereafter adding said acrylamide.

3. The process of claim 2 wherein said salt is acetamidine hydrochloride.

* l l i 

1. A PROCESS FOR PRODUCING 4-AMINO-2-METHYLPYRIMIDINE-5CARBOXAMIDE COMPRISING THE STEPS OF REACTING 3-DI(LOWER ALKYL)AMINO-2-CYANOACRYLAMIDE OF THE FORMULA:
 2. The process of claim 1 wherein said mixture is prepared by first neutralizing in an inert organic solvent a hydrohalic acid addition salt of acetamidine with a base and thereafter adding said acrylamide.
 3. The process of claim 2 wherein said salt is acetamidine hydrochloride. 